Psoriasis and other pathological skin diseases have typically been considered as immune-driven diseases. While several key cellular and cytokine pathways have been identified that are critical to psoriasis pathology, many mechanisms still remain unknown particularly due to the lack of good experimental models for psoriasis. Recently, topical treatment of skin with a toll-like receptor agonist, which physiologically mimics the release of self-nucleic acids and/or viral infection, has been shown to result in psoriasis-lik pathology in mice. Using this model, our exciting preliminary data suggests a critical role for sensory innervation in the skin as an instigator and promoter of skin immunopathology. As a result, the specific aims of this proposal will aim to mechanistically link how sensory neurons control immune responses in the skin, particularly within the context of a model of psoriasis. Due to the recent description of the importance of dermal ? T cells in this model, a subset of cells that is skin-resident and primed to respond rapidly to cytokine signals, we hypothesize that sensory neurons may directly or indirectly communicate with ? T cells in order to regulate their function. The first aim of this proposal will seek to characterize how sensory denervation alters dermal ? T cell phenotype and function. Based on the data gathered from Aim 1 and several intriguing clues gathered from the literature, Aim 2 will investigate how known factors released from sensory neurons regulate the production of cytokines and mediators which are known triggers of ? T cells. The successful completion of these two complementary aims will provide a mechanistic understanding of how sensory neurons control a cascade of immune mediators culminating in dermal ? T cell activation and, of clinical relevance, the generation of psoriatic lesions. Unraveling the complex web of neuro-immune interactions within a tissue that is commonly involved in misdirected immune responses resulting in severe and debilitating disease will provide novel therapeutic targets for immunomodulation of skin disease. In some situations, such as vaccination, a better understanding of the cues which control T-cell fate decisions will help to design vaccines that can promote memory that is both skin-resident and protective. Finally, due to the importance of ? T cell-derived cytokines in recruiting neutrophils to combat cutaneous infections, such as Staphylococcus aureus, an understanding of the endogenous triggers which activate ? T cells will lead to potentially novel and unprecedented therapies for the treatment of ongoing infections where host defense is compromised.